Process for the manufacture of organic compounds

ABSTRACT

A method for preparing an alkali metal salt comprising: (a) condensing a disilyloxydiene with an aldehyde in the presence of a titanium (IV) catalyst in an inert solvent to form a 5(S)-hydroxy-3-ketoester; (b) reducing the 5(S)-hydroxy-3-ketoester to a 3(R),5(S)-dihydroxyester in the presence of a di(lower alkyl)methoxyborane; and (c) hydrolyzing the 3(R),5(S)-dihydroxyester in the presence of an aqueous base to form an alkali metal salt.

This application claims the benefit of U.S. Provisional Application No.60/352,316, filed Jan. 28, 2002, and U.S. Provisional Application No.60/383,188, filed May 24, 2002 which in their entirety are hereinincorporated by reference.

In one embodiment, the invention provides an enantioselective method forpreparing compounds having Formula (S₁), (S₂), or (S₃) as follows:

wherein

-   -   R₁ is independently an unsubstituted or substituted alkyl,        cycloalkyl or aralkyl; and    -   R₂, R₃, R₄, R₅, R₆ and R₇ are, independently, hydrogen, halogen,        hydroxy, optionally substituted alkyl, cycloalkyl, aryl,        aralkyl, heterocyclyl, heteroaralkyl, optionally substituted        alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy.

Listed below are definitions of various terms used to describe thecompounds of the instant invention. These definitions apply to the termsas they are used throughout the specification unless they are otherwiselimited in specific instances either individually or as part of a largergroup.

The term “optionally substituted alkyl” refers to unsubstituted orsubstituted straight or branched chain hydrocarbon groups having 1-20carbon atoms, preferably 1-7 carbon atoms. Exemplary unsubstituted alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl andthe like. Substituted alkyl groups include, but are not limited to,alkyl groups substituted by one or more of the following groups: halo,hydroxy, cycloalkyl, alkoxy, alkenyl, alkynyl, alkylthio, alkylthiono,sulfonyl, nitro, cyano, alkoxycarbonyl, aryl, aralkoxy, heterocyclylincluding indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl,pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.

The term “lower alkyl” refers to those alkyl groups as described abovehaving 1-7 carbon atoms, preferably 1-4 carbon atoms.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “alkenyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing at least one carbon tocarbon double bond at the attachment point. Groups having 2-4 carbonatoms are preferred.

The term “alkynyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing at least one carbon tocarbon triple bond at the attachment point. Groups having 2-4 carbonatoms are preferred.

The term “cycloalkyl” refers to optionally substituted monocyclic,bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each ofwhich may be substituted by one or more substituents, such as alkyl,halo, oxo, hydroxy, alkoxy, alkylthio, nitro, cyano, alkoxycarbonyl,sulfonyl, heterocyclyl and the like.

Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like.

Exemplary bicyclic hydrocarbon groups include bornyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like.

Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

The term “alkoxy” refers to alkyl-O—.

The term “alkylthio” refers to alkyl-S—.

The term “alkylthiono” refers to alkyl-S(O)—.

The term “trialkylsilyl” refers to (alkyl)₃Si—.

The term “trialkylsilyloxy” refers to (alkyl)₃SiO—.

The term “alkylsulfonyl” refers to alkyl-S(O)₂—.

The term “sulfonyl” refers to alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-12 carbon atoms in the ring portion, such as phenyl,naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each ofwhich may optionally be substituted by 1-4 substituents, such as alkyl,halo, hydroxy, alkoxy, acyl, thiol, alkylthio, nitro, cyano, sulfonyl,heterocyclyl and the like.

The term “monocyclic aryl” refers to optionally substituted phenyl asdescribed under aryl.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl.

The term “aralkylthio” refers to aralkyl-S—.

The term “aralkoxy” refers to an aryl group bonded directly through analkoxy group.

The term “arylsulfonyl” refers to aryl-S(O)₂—.

The term “arylthio” refers to aryl-S—.

The term “heterocyclyl” or “heterocyclo” refers to an optionallysubstituted, fully saturated or unsaturated, aromatic or nonaromaticcyclic group, for example, which is a 4- to 7-membered monocyclic, 7- to12-membered bicyclic or 10- to 15-membered tricyclic ring system, whichhas at least one heteroatom in at least one carbon atom-containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized. The heterocyclic group may be attached at a heteroatom or acarbon atom.

The term “heteroaryl” refers to an aromatic heterocycle, e.g.,monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl,benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzofuryl and the like, optionally substituted by, e.g., lower alkyl,lower alkoxy or halo.

The term “heteroarylsulfonyl” refers to heteroaryl-S(O)₂—.

The term “heteroaralkyl” refers to a heteroaryl group bonded through analkyl group.

Accordingly, compounds having Formula (S₁), (S₂), or (S₃) may beprepared by first condensing a disilyloxydiene having Formula (II)

wherein

-   -   R₁ is independently an unsubstituted or substituted alkyl,        cycloalkyl or aralkyl; and    -   R and R′ represent lower alkyl, preferably ethyl or methyl, and        R and R′ may be identical or different,        with an aldehyde having Formula (Q₁), (Q₂), or (Q₃) as follows:

wherein R₂, R₃, R₄, R₅, R₆ and R₇ have meanings as defined for Formula(S₁), (S₂), or (S₃) in the presence of a titanium (IV) catalyst havingFormula (IV)

wherein R₈ is a lower alkyl, and the binaphthyl moiety is in theS-configuration, in an inert solvent to obtain compounds having Formula(S₁), (S₂), or (S₃) in high chemical yield and enantiomeric purity.

In the aldol condensation above the molar ratio of a disilyloxydiene ofFormula (II) to an aldehyde having Formula (Q₁), (Q₂), or (Q₃) initiallypresent in the reaction mixture ranges from 1:1 to 6:1, preferably from1:1 to 4:1, and more preferably from 1.5:1 to 3:1.

The disilyloxydiene of Formula (II) may be prepared by reacting anacetoacetate of having Formula (VI)

wherein R₁ is independently an unsubstituted or substituted alkyl,cycloalkyl or aralkyl; with a silylating agent, such as tri(loweralkyl)silyl chloride or tri(lower alkyl)silyl trifluoromethanesulfonate,preferably trimethylsilyl chloride or triethylsilyl chloride, in thepresence of a base, such as triethylamine, diisopropylethylamine orN-methylmorpholine, preferably triethylamine, in an organic solvent,such as pentane, hexane, heptane, tetrahydrofuran, diethyl ether ordichloromethane, preferably hexane, at a temperature ranging from about−25° C. to about 30° C. to form a silylenolether of the Formula (VII)

wherein

-   -   R₁ is independently an unsubstituted or substituted alkyl,        cycloalkyl or aralkyl; and    -   R is a lower alkyl.

The silylenolether of Formula (VII) may then be treated with a base,such as lithium diisopropylamide or lithium, sodium or potassiumbis(trimethylsilyl)amide, preferably lithium diisopropylamide, followedby addition of a silylating agent, such as tri(lower alkyl)silylchloride or tri(lower alkyl)silyl trifluoromethanesulfonacte, preferablytrimethylsilyl chloride or triethylsilyl chloride, in an inert solvent,such as diethylether or tetrahydrofuran, preferably tetrahydrofuran, ata temperature ranging from about −40° C. to about −100° C. to form thedisilyloxydiene of Formula (II).

Lithium diisopropylamide may be generated in situ from diisopropylamineand n-butyllithium under conditions well-known in the art or asillustrated in the examples herein.

The molar ratio of the titanium (IV) catalyst of Formula (IV) to analdehyde of Formula (II) initially present in the aldol condensationabove ranges from 0.01:1 to 0.15:1, preferably from 0.04:1 to 0.1:1.

The titanium (IV) catalyst of Formula (IV) may be prepared in situ byreacting Ti(OR₈)₄, in which R₈ is lower alkyl, preferably isopropyl,with (S)-2,2′-binaphthol of the Formula (VIII)

(S)-2,2′-Binaphthol of Formula (VIII) is commercially available, e.g.,from Karlshamns under the trademark BINOL, and titanium (IV)tetra-alkoxides, preferably titanium (IV) tetraisopropoxide, mayoptionally be generated in situ from titanium tetrachloride and sodiumor lithium alkoxide, preferably sodium or lithium isopropoxide.

The aldol condensation above may be carried out in a polar aproticsolvent, such as tetrahydrofuran, diethylether or dimethoxyethane,preferably tetrahydrofuran. A combination of solvents may also be used.The reaction temperature may range from about 0° C. to about 70° C.,preferably from about 10° C. to about 60° C., and more preferably fromabout 15° C. to about 55° C. The reaction is conducted for a period oftime from about 1 hour to about 72 hours, preferably from about 2 hoursto about 24 hours.

The compounds having Formula (S₁), (S₂), or (S₃) may optionally bepurified by physical or chemical means to enrich the enantiomericpurity. Examples of such means for enrichment include, but are notlimited to, crystallization and chiral preparative chromatography, suchas high pressure liquid chromatography (HPLC).

In another embodiment, the invention provides a stereoselective methodfor the preparation of syn-3(R),5(S)-dihydroxyesters by reducingcompounds of Formula (S₁), (S₂), or (S₃). Thesyn-3(R),5(S)-dihydroxyesters have Formula (V₁), (V₂), or (V₃) asfollows:

mixture wherein

-   -   R₁ is, independently, an unsubstituted or substituted alkyl,        cycloalkyl or aralkyl; and    -   R₂, R₃, R₄, R₅, R₆ and R₇ are, independently, hydrogen, halogen,        hydroxy, optionally substituted alkyl, cycloalkyl, aryl,        aralkyl, heterocyclyl, heteroaralkyl, optionally substituted        alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy.

The stereoselective reduction of compounds having Formula (S₁), (S₂), or(S₃) may be achieved in the presence of a di(lower alkyl)methoxyborane,such as diethylmethoxyborane or dibutyl-methoxyborane, preferablydiethylmethoxyborane, in a polar solvent, such as tetrahydrofuran orlower alcohol, e.g., methanol or ethanol, or a of solvents thereof,preferably a mixture of tetrahydrofuran and methanol. The reducing agentused in the reduction step above may be selected from a group of hydridereagents, such as sodium and lithium borohydride. Preferably thereducing agent is sodium borohydride. The reaction may be conducted at atemperature ranging from about −20° C. to about −100° C., preferablyfrom about −50° C. to about −80° C.

In another embodiment, the invention provides methods for thepreparation of calcium salts having Formula (We), (W₂), or (W₃) asfollows:

wherein R₂, R₃, R₄, R₅, R₆ and R₇ are, independently, hydrogen, halogen:hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy,aralkoxy, heterocyclooxy or heteroaralkoxy.

Calcium salts of Formula (W₁), (W₂), or (W₃) may be prepared by firsthydrolyzing compounds of Formula (V₁), (V₂), or (V₃) in the presence ofan aqueous base to form the corresponding alkali metal salts havingFormula (X₁), (X₂), or (X₃) as follows:

wherein R₂, R₃, R₄, R₅, R₆ and R₇ are, independently, hydrogen, halogen,hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy,aralkoxy, heterocyclooxy or heteroaralkoxy; and M is sodium, lithium orpotassium, preferably sodium.

The hydrolysis step above may be carried out in an organic solvent, suchas a lower alcohol, preferably ethanol, and the base used in saidhydrolysis is preferably selected from aqueous potassium hydroxide,aqueous lithium hydroxide and aqueous sodium hydroxide. More preferably,the base is sodium hydroxide. The hydrolysis is preferably conducted ata temperature ranging from about −10° C. to about 30° C., preferablyfrom about 0° C. to about 25° C.

Alkali metal salts having Formula (X₁), (X₂), or (X₃) may then beconverted to corresponding calcium salts of Formula (W₁), (W₂), or (W₃),by reacting an aqueous solution of an alkali metal salt of Formula (X₁),(X₂), or (X₃) with an aqueous solution of a suitable calcium source atan ambient temperature, preferably at room temperature. Suitable calciumsources include, but are not limited to, calcium chloride, calcium oxideand calcium hydroxide.

Alternatively, calcium salts of Formula (W₁), (W₂), or (W₃) may beobtained by first cyclizing compounds of Formula (V₁), (V₂), or (V₃) inthe presence of an acid and an aprotic water-miscible solvent to formthe corresponding lactone having Formula (Y₁), (Y₂), or (Y₃) as follows:

and acid addition salts thereof;wherein R₂, R₃, R₄, R₅, R₆ and R₇ are, independently, hydrogen, halogen,hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy,aralkoxy, heterocyclooxy or heteroaralkoxy.

The cyclization above may be carried out in the presence of an acid,such as trifluoroacetic acid or a strong mineral acid, preferablyconcentrated hydrochloric acid, in an aprotic water-miscible solventsuch tetrahydrofuran or acetonitrile, preferably acetonitrile, at atemperature ranging from 0-25° C. Lactones of Formula (Y₁), (Y₂), or(Y₃), and acid addition salts thereof, preferably hydrochloric acidsalts thereof, may contain small amounts of the unreacted startingmaterial of Formula (V₁), (V₂), or (V₃); and the corresponding acidhaving Formula (Z₁), (Z₂), or (Z₃) as follows:

and acid addition salts thereof, preferably hydrochloric acid saltsthereof;wherein R₂, R₃, R₄, R₅, R₆ and R₇ are, independently, hydrogen, halogen,hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy,aralkoxy, heterocyclooxy or heteroaralkoxy.

Lactones of Formula (Y₁), (Y₂), or (Y₃), contaminants thereof, and acidaddition salts thereof, may then be converted to the correspondingcalcium salts of Formula (W₁), (W₂), or (W₃) analogously as describedherein above for compounds of Formula (V₁), (V₂), or (V₃), ormodifications thereof.

In one embodiment of the invention, the calcium salt is pitavastatincalcium.

The processes described herein above are conducted under inertatmosphere, preferably under nitrogen atmosphere. It is within the scopeof the invention to use a molecular sieve during the preparation of thecompounds of the invention, especially in the step of condensing adisilyloxydiene with an aldehyde of Formula (Q₁), (Q₂), or (Q₃), in thepresence of a titanium (IV) catalyst. Water may optionally be added tothe molecular sieve prior to using the molecular sieve. In oneembodiment, the water content of the molecular sieve is preferably fromabout 1 wt % to about 15 wt %, more preferably from about 2.6 wt % toabout 10 wt %, based on the total weight of the titanium (IV) catalyst.

The type of reactor used to prepare the compounds of the inventioninclude batch, continuous, and semicontinuous reactors. It is within thescope of the invention to prepare the compounds in an external recyclereactor which allows: (i) in-situ pre-treatment or post-treatment of thesolid mol sieves (ii) elimination of mole sieves filtration at the endof the reaction and (iii) easy re-use of the mol sieves for possiblemulticycle operation.

In starting compounds and intermediates, which are converted to thecompounds of the invention in a manner described herein, functionalgroups present, such as amino, thiol, carboxyl and hydroxy groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected amino, thiol, carboxyl andhydroxyl groups are those that can be converted under mild conditionsinto free amino thiol, carboxyl and hydroxyl groups without themolecular framework being destroyed or other undesired side reactionstaking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxyl group,amino group, etc.), the structure and stability of the molecule of whichthe substituent is a part and the reaction conditions. Well-knownprotecting groups that meet these conditions and their introduction andremoval are described, e.g., in McOmie, “Protective Groups in OrganicChemistry”, Plenum Press, London, N.Y. (1973); and Greene, “ProtectiveGroups in Organic Synthesis”, Wiley, NY (1991).

The compounds of the invention may be prepared in high enantiomericpurity, and therefor, eliminate the need for resolution. As used herein,high enantiomeric purity or enantioselectivity means at least 70%optical purity, preferably at least 80% optical purity, most preferablyat least 97% optical purity.

The compounds of the invention are especially useful for treating orpreventing atherosclerosis. In one embodiment of the invention, thecompounds inhibit the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A(HMG-CoA) reductase which has been identified as a rate-limiting enzymein the cholesterol biosynthetic pathway.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 and 100mmHg (=20-133 mbar). The structure of final products, intermediates andstarting materials is confirmed by standard analytical methods, e.g.,microanalysis, melting point (mp) and spectroscopic characteristics,e.g., MS, IR and NMR. Abbreviations used are those conventional in theart.

EXAMPLE 1 Preparation of 3-trimethylsilanyloxy-but-2-enoic acid ethylester

A solution of 31.9 mL (0.25 mole) of ethyl acetoacetate is stirred inhexane (350 mL) at room temperature. Triethylamine (42 mL, 0.30 mole) isadded, followed by dropwise addition of trimethylsilyl chloride (35 mL,0.276 mole) keeping the internal temperature below 25° C. using a waterbath (about 18° C.). The thick white slurry is stirred overnight at roomtemperature. 200 mL of hexane is then added and the mixture stirred inan ice bath for 1 hour. The mixture is filtered and the solids arewashed with 50 mL of cold hexane. Evaporation of the combined filtrateand washings gives 46 g of 3-trimethylsilanyloxy-but-2-enoic acid ethylester as a colorless, slightly cloudy oil. This material is used withoutfurther purification in the following step.

EXAMPLE 2 Preparation of1-ethoxy-1,3-bis-trimethylsilanyloxy-buta-1,3-diene

Under nitrogen atmosphere, 600 mL of anhydrous tetrahydrofuran and 38 mLof diisopropylamine (0.271 mole) is cooled to −5° C. 121 mL of 2.5 Mn-butyllithium (in hexane) is added while keeping the internaltemperature at −3±3° C. The mixture is then cooled to −78° C. with a dryice acetone bath. 45.2 g (0.22 mole) of the compound of Example 1,3-trimethylsilanyloxy-but-2-enoic acid ethyl ester is added, keeping theinternal temperature below −70° C. After stirring 25 minutes, 44 mL oftrimethylsilyl chloride (0.347 mole) is added while keeping the internaltemperature below −70° C. The mixture is then allowed to warm up to roomtemperature. After evaporation of solvents, the residue is stirred in250 mL of hexane, cooled with an ice bath and stirred for 1 hour,followed by filtration to remove solids. The filtrate is evaporated toobtain 64.7 g of 1-ethoxy-1,3-bis-trimethyl-silanyloxy-buta-1,3-diene asa yellow oil, which is used without further purification in thefollowing step. The material is protected from moisture and stored in afreezer (−35° C.).

EXAMPLE 3 Preparation of(E)-(5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid ethyl ester

Method 1:

To a dry 500 mL flask under nitrogen atmosphere are charged 25.4 g of(E)-3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-propenal,prepared according to a process described in “Synthesis and BiologicalEvaluations of Quinoline-based HMG-CoA Reductase Inhibitors”, BioorganicMed. Chem., Vol. 9, pp. 2727-2743 (2001), 0.080 mole, 0.91 g (S)-BINOL(4 mole %) and 5 g of molecular sieves (4A activated powder). 200 mL ofanhydrous tetrahydrofuran is added and the mixture is stirred for 40minutes 0.95 mL (4 mole %) of titanium (IV) isopropoxide is then addeddropwise. The mixture becomes dark red immediately. After stirring 30minutes at room temperature, 39.2 g (about 44 mL, 0.143 mole) of thecompound of Example 2,1-ethoxy-1,3-bis-trimethylsilanyloxy-buta-1,3-diene is added dropwiseover 10 minutes. The flask is kept in a 18° C. water bath to maintain aninternal temperature below 25° C. The mixture is stirred at roomtemperature and the disappearance of(E)-3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-propenal ismonitored by TLC (33% ethyl acetate/hexane, R_(f) aldehyde=0.65).Reaction time varies from 1 hour to 72 hours depending on the amount ofcatalyst used. After the reaction is complete, 50 mL of water is addedand the mixture is cooled with an ice bath, then 10 mL of 1:1(^(v):_(v)) trifluoroacetic acid/water is added. The mixture is allowedto warm to room temperature over about 30 minutes. At this timedesilyation is complete as judged by TLC (disappearance of silyloxyaldol adduct R_(f)=0.75, appearance of desilylated product R_(f)=0.22).The mixture is added to a rapidly stirred flask containing 400 mL ofethyl acetate and 100 mL of saturated aqueous sodium bicarbonate. Afterstirring 5 minutes, the mixture is filtered to remove molecular sieves.The organic layer is separated and washed with brine, dried overanhydrous sodium sulfate and filtered. After solvent removal byevaporation, about 150 mL of hexane is added to the resulting oil over45 minutes to induce precipitation. The mixture is stirred in an icebath for additional 45 minutes. The precipitated solids are collected byvacuum filtration, washed with cold hexane and dried overnight undervacuum at 35° C. to form 33.8 g (94%) of(E)-(5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid ethyl ester in 97.4% optical purity (HPLC: Chiralpak AD; eluent,hexane/i-PrOH—94/6; flow rate 1 mL/min.; UV @254 nM).

Method 2:

Under nitrogen a dry 1,000 mL flask is charged with 1.44 g of (S)-BINOL,14.8 g of molecular sieves 4A powder (previously stored for at least 24hours in an ordinary convection oven at 110° C.), and 210 mL ofanhydrous tetrahydrofuran. The mixture is stirred at 20±2° C. for about15 minutes, then 1.49 mL of titanium (IV) isopropoxide is added dropwiseand the dark red mixture is warmed to 50±1° C. and stirred for 30minutes, then cooled back to 20±2° C. 32.0 g of(2E)-3-{2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl}-2-propenal isadded as a solid and the mixture stirred for 10 minutes. Five portionsof 64.6 g (about 71 mL) of the compound of Example 2,1-ethoxy-1,3-bis-trimethylsilanyloxy-buta-1,3-diene are then added,adding each portion over about 5 minutes (mildly exothermic) and waiting30 minutes before adding the next portion. The internal temperature ismaintained at 20±2° C. Disappearance of aldehyde is monitored by TLC(2:1 (^(v)/_(v)) hexane/EtOAc, R_(f) aldehyde=0.65). When the reactionis complete, the mixture is cooled with an ice bath and 40 mL of 20%(^(v)/_(v)) aqueous trifluoroacetic acid is added. The mixture is warmedto room temperature. After 30 minutes, the desilylation is judgedcomplete by TLC (disappearance of silyloxy aldol adduct R_(f)=0.75,appearance of de-silylated product R_(f)=0.22). The mixture is cooledwith an ice bath and 80 g of 25% (^(v)/_(v)) aqueous phosphoric acid isadded (exothermic) while maintaining the internal temperature below 25°C. The mixture is stirred for 3 hours, then the layers are separated.The aqueous layer is extracted with 210 mL of t-butyl methyl ether andthe organic layers are combined and washed with 4×150 mL of 10% aqueoussodium chloride. Solvents are removed by rotoevaporation and theresulting oil is dissolved in 150 mL of n-butanol and evaporated underreduced pressure. This process is repeated with an additional 150 mL ofn-butanol to form(E)-(5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid ethyl ester in 99.3% optical purity (HPLC: Chiralpak AD; eluent,hexane/i-PrOH—94/6; flow rate 1 mL/min.; UV @ 254 nM). The product maybe used in the next step without further purification.

It is possible to prepare molecular sieves 4A powder at othertemperatures and also to add the appropriate amount of water to the THFsolution of (S)-BINOL and molecular sieves (MS) in order to adjust thewater content to the desired range. The effect on optical purity ofthese factors as well as the ratio of MS to (S)-BINOL is shown in thefollowing table:

MS: (S)-Binol Optical MS preparation ratio (^(w)/_(w)) Purity (%) Storedin 110° C. oven >24 hours 2.6 89.4 Commercially Purchased Activated MS4.2 95.8 Stored in 140° C. oven >24 hours 4.2 97.6 Stored in 110° C.oven >24 hours 4.2 98.4 Stored in 65° C. oven >24 hours 4.2 98.4 Storedin 110° C. oven >24 hours 4.8 98.7 Stored in 110° C. oven >24 hours 1099.0-99.6 MS dried to 6.1% (w/w) water content at 125° C. 10 96.4 underdry N₂ MS dried to 8.9% (w/w) water content at 125° C. 10 98.5 under dryN₂ MS with 6.1% (w/w) H₂O content and 6.1% H₂O 10 98.9 added

Method 3:

Under argon a dry 350-mL flask is charged with 0.92 g (S)-BINOL (5 mol%), 9.24 g relatively dry molecular sieves (4A activated powder; watercontent: 1.0%) and 130 mL of aqueous tetrahydrofuran containing 462 μLof water. This mixture is stirred at 20-25° C. for 1 hour, then 0.96 mLof titanium (IV) isopropoxide (5 mol %) is added dropwise and the darkred mixture is warmed to 50±1° C. and stirred for 30 min, then cooledback to 20±2° C. 20 g of(2E)-3-[2-cyclopropyl-4-(4-fluorphenyl)-quinolin-3-yl]-2-propenal (0.063mol) is added as a solid and the mixture stirred for 10 min. Sevenportions of 56.56 g (about 62 mL, 0.206 mol) of the compound of Example2, 1-ethoxy-1,3-bis-trimethylsilanyloxy-buta-1,3-diene are then added,adding each portion over about 5 min (mildly exothermic) and waiting 30min before adding the next portion. The internal temperature ismaintained at 20±2° C. Disappearance of aldehyde is monitored by TLC(2:1 (v/v) hexane/EtOAc, R_(f) aldehyde=0.65). When the reaction iscomplete, the mixture is cooled with an ice bath and 150 g of 25%aqueous phosphoric acid is added (exothermic) within 10 min whilemaintaining the internal temperature below 25° C. The mixture is stirredfor 1 hour at 20-25° C. The desilylation is judged complete by TLC(disappearance of silyloxy aldol adduct R_(f)=0.75, appearance ofdesilylated product R_(f)=0.22). Afterwards the layers are separated.The organic layer is extracted with 87 g of 25% aqueous phosphoric acid.The combined aqueous layers are extracted with 2×130 mL of t-butylmethyl ether and the organic layers are combined and washed with 4×76 mLof 10% aqueous sodium chloride. Solvents are evaporated under reducedpressure, the resulting oil is dissolved in 100 mL of n-butanol and thesolution is evaporated again under reduced pressure. This process isrepeated with an additional 100 mL of n-butanol to yield 49.4 g of anoily residue. 247 g of heptane fraction are added to this oil and themixture is warmed to 45° C.±1° C. and stirred for 1 hour. After coolingto 0-5° C. the mixture is stirred for another hour at that temperature.The precipitated solids are collected by vacuum filtration, washed with2×30 mL heptane fraction and dried overnight under vacuum at 60° C. toafford 26.3 g (89%) of(E)-(5S)-7-[2-cyclopropyl-4-4-fluorophenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid ethyl ester in 99.7% optical purity (HPLC: Chiralpak AD-H; eluentn-hexane/ethanol 90/10; flow rate 1.0 mL/min; T=30° C.; detection UV at244 nm) and 95.7% chemical purity (HPLC: YMC-Pack ODS-AQ; eluent 0.01 Maqueous ammonium acetate solution/acetonitrile 45/55; flow rate 0.7mL/min; T=60° C.; detection UV at 245 nm).

EXAMPLE 4 Preparation of(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid ethyl ester

To a dry, 1 L flask in a dry ice acetone bath under nitrogen atmosphereare added 4.16 g of sodium borohydride (0.11 mole) and 300 mL oftetrahydrofuran. The mixture is stirred for about 30 minutes afterinternal temperature is below −70° C. 10.8 mL of diethyl-methoxyborane(0.082 mole) is added dropwise over about 10 minutes. The mixture isstirred for 15 minutes, then a solution of 30 g of the compound ofExample 3,(E)-(5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid ethyl ester (Method 1, 0.067 mole) in 60 mL of tetrahydrofuran and100 mL of methanol is added dropwise over about 30 minutes keeping theinternal temperature below −70° C. After 30 minutes, the mixture iswarmed up to room temperature and added to a rapidly stirred flaskcontaining 200 mL of saturated aqueous sodium bicarbonate and 400 mL ofethyl acetate. After mixing, the layers are separated. The organicsolution is concentrated, and the residue is dissolved in 400 mL ofethyl acetate, to which is slowly added 70 mL of 30% (^(w):_(w)) aqueoushydrogen peroxide, using a cooling bath to keep the internal temperaturebelow 25° C. After stirring for 1 hour at room temperature, stirring isdiscontinued and the layers are separated. The organic layer is washedwith 150 mL saturated sodium sulfite followed by 150 mL of brine towhich 15 mL of saturated aqueous sodium bicarbonate is added. Afterevaporation of solvents from the organic layer, the resulting oil isdistilled with toluene followed by heptane to obtain a crude oil in97.2% optical purity (HPLC: Chiralpak AD; eluent, hexane/i-PrOH—94/6;flow rate 1 mL/min.; UV @ 254 nM). The oil is dissolved in 330 mL of90:10 (^(v)/_(v)) cyclohexane/methyl-t-butyl ether at 45° C. Cooling toroom temperature and stirring overnight results in the formation of asmall amount of solids. By filtering off the solids the optical purityof the product remaining in the mother liquor is enriched to 99.3%.Evaporation of the mother liquor gives a thick oil which is purified bysilica gel chromatography (ethyl acetate/hexanes) to form 20.8 g of(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid ethyl ester as a white solid in 99.3% optical purity.

EXAMPLE 5 Preparation of(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid calcium salt, pitavastatin calcium, Method 1

Under a nitrogen atmosphere, to a 250 mL flask are added 5.75 g (0.0128mole) of the compound of Example 4,(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid ethyl ester and 40 mL of ethyl alcohol. The mixture is stirreduntil a clear yellow solution is formed. The solution is then cooled toan internal temperature in a range of 0-3° C., and 2.6 mL of 5 N aqueoussodium hydroxide solution (0.0128 mole) is added dropwise. The reactionis held at this temperature for 45 minutes. TLC (ethyl acetate/hexane3:7) shows that the starting material has disappeared and the reactionis complete. The solvent is removed on a rotary evaporator at atemperature less than 45° C. 75 mL of water and 50 mL of methyl-t-butylether are added to the residue, and the mixture is stirred for 10minutes, the layers are separated and the aqueous layer is washed twicewith 50 mL of methyl-t-butyl ether. To completely remove organicsolvent, the aqueous solution is concentrated to 20 mL with a rotaryevaporator (water bath<45° C.), 50 mL of water is added to the residue,and the solution is re-distilled to 20 mL volume, and again 50 mL ofwater is added, then re-distilled to 20 mL under the same condition. 200mL of water is added to the residue to form a light-yellow clear sodiumsalt solution. A solution of 1.035 g of calcium chloride dihydrate(0.007 mole) in 20 mL of water is added to the sodium salt solutionwhile vigorously stirring. The solution immediately changes to a whiteslurry. Stirring is continued for 3 hours further. The solid iscollected by filtration, washed 3 times with 50 mL of water and dried at35° C. in a vacuum oven to obtain pitavastatin calcium in 99.4% opticalpurity (HPLC: Chiralpak AD; eluent, hexane/i-PrOH—94/6; flow rate 1mL/min.; UV @ 254 nM).

EXAMPLE 6 Preparation of(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid calcium salt, Pitavastatin calcium, Method 2

A.6-[2-{2-Cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl}-E-ethylenyl]-tetrahyhydro-4-hydroxy-4R-trans)-2H-pyranonehydrochloric acid salt

A solution of the compound of Example 5,(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid ethyl ester (45.4 g, 0.101 mole) in 400 mL of MeCN is added to amixture of 11.2 mL of concentrated HCl acid and 400 mL of MeCN whilemaintaining the reaction temperature at 20±2° C. After stirring for 3hours further at 20±2° C., a precipitate is formed and the reaction iscooled to 0±2° C. over 1 hour. The mixture is stirred for 2 hoursfurther at 0±2° C., and the solids are collected by vacuum filtration,washed with 100 mL of MeCN, and dried under vacuum to form 37.7 g (85%)of6-[2-{2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl}-E-ethylenyl]-tetrahyhydro-4-hydroxy-4R-trans)-2H-pyranonehydrochloric acid salt.

B.(E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid calcium salt, Pitavastatin calcium

Under a nitrogen atmosphere, 10.0 g (0.0227 mole) of6-[2-{2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl}-E-ethylenyl]-tetrahyhydro-4-hydroxy-4R-trans)-2H-pyranonehydrochloric acid salt is suspended in 250 mL of water, and 9.1 mL(0.0455 mole) of aqueous 5 N sodium hydroxide is added. The mixture isstirred until dissolution is complete (about 2 hours), then filteredthrough celite. The filtrate is washed three times with 100 mL ofmethyl-t-butyl ether and the organic washings are discarded. Tocompletely remove methyl-t-butyl ether, the aqueous solution isconcentrated to about 40 mL under reduced pressure (water bath<45° C.)and readjusted to 400 mL. A solution of 1.84 g of calcium chloridedihydrate (0.0125 mole) in 20 mL of water is added to the sodium saltsolution while vigorously stirring. The solution immediately changes toa white slurry. Stirring is continued to for at least 2 hours further.The solids are collected by filtration, washed with 100 mL of water andthe solids are suspended in 75 mL of water and 320 mL of isopropahol.The mixture is heated at reflux until a homogeneous solution isobtained. The solution is cooled to room temperature and stirred for 18hours. The resulting slurry is cooled to 1-3° C. and held at thistemperature for 3 hours. The solids are collected by vacuum filtration,washed three times with 20 mL of water and dried at 55° C. in a vacuumoven to obtain 6.5 g (65%) of pitavastatin calcium in 99.9% opticalpurity (HPLC: Chiralcel OD; eluent, hexane/EtOH/TFA—900/100/0.5; flowrate 1 mL/min.; UV @ 254 nM).

EXAMPLE 7 Preparation of(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid calcium salt, pitavastatin calcium, Method 3

A.6-[2-{2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl}-E-ethylenyl]-tetrahyhydro-4-hydroxy-4R-trans)-2H-pyran-onehydrochloric acid salt

In a 20 L reactor under nitrogen atmosphere dry tetrahydrofuran (2.6 L)is cooled to −68° C. and sodium borohyride (106.3 g, 2.78 mole) isadded. When the internal temperature reached −75° C., diethylmethoxyborane (430 g, 2.14 mole, 50% solution in tetrahydrofuran) isadded over 20 minutes followed by 140 mL of tetrahydrofuran. The whitesuspension is stirred for 30 minutes, then a solution of the compoundproduced like in Example 3, Method 3 (498.5 g, 1.07 mole) in 900 mLtetrahydrofuran and 900 mL methanol is added dropwise over 3 hourskeeping the internal temperature below −70° C. The mixture is stirredfor 1 hour at this temperature and then warmed up to 0° C. A sodiumhydrogen carbonate solution 5% (5.3 L) is added, followed by 2 L ofisopropylacetate. After vigorous stirring for 10 minutes at 20° C.,stirring is discontinued and the layers are separated. The aqueous phaseis re-extracted with 800 mL of isopropylacetate. After evaporation ofsolvents from the combined organic layer at 30-40° C., the resulting oilis dissolved in 2 L of isopropylacetate. Hydrogenperoxide 30% (263 mL,2.5 mole) is added over 20 minutes, keeping the internal temperature at20° C. and the mixture is stirred for 2 hours. After addition of brine(1 L) the layers are separated and the aqueous layer is re-extractedwith 250 mL of isopropylacetate. To the combined organic layer, aqueoussodium sulfit (2 L, 8% solution) is added and stirred for 30 minutesuntil a peroxide test is negative. After separation of the layers, theorganic layer is washed with 1 L of water and evaporated to dryness at30-40° C. Under vacuum. The resulting oil is dissolved in 3.2 L ofacetonitrile, evaporated to dryness, re-dissolved in 2 L of acetonitriland filtered through celite. This solution is added over 20 minutes to amixture of 37% hydrochloric acid (142 g, 1.44 mole) in 3 L acetonitrile.After seeding the mixture is stirred for 3 hours at 20° C. and overnight at 0-5° C. The solid is filtered off, washed with 840 mL coldacetonitrile and dried at 35° C. in a vacuum oven to afford 389 g (82%)of6-[2-{2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl}-E-ethylenyl]-tetrahyhydro-4-hydroxy-4R-trans)-2H-pyranonehydrochloric acid salt as a pale orange powder.

B.(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid calcium salt, pitavastatin calcium

Under a nitrogen atmosphere, 388 g (0.873 mole) of the6-[2-{2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl}-E-ethylenyl]-tetrahyhydro-4-hydroxy-4R-trans)-2H-pyranonehydrochloric acid salt is suspended in 9.6 L of water, and 349 mL (1.746mole) of aqueous 5 N sodium hydroxide is added. The mixture is stirredfor 2 hours, then filtered through celite and washed with 2 L of water.The filtrate is washed three times with 3.8 L (=11.4 L) of ethylacetateand the organic washings are discarded. To completely removeethylacetate, the aqueous solution is concentrated to about 11 L underreduced pressure at 35-40° C. A solution of 70.61 g of calcium chloridedihydrate (0.480 mole) in 786 mL of water is added to the sodium saltsolution while vigorously stirring. The solution immediately changes toa white slurry. Stirring is continued to for at least 2 hours further.The solids are collected by filtration, washed with 2 L of water anddried at 40° C./20 mbar for 24 hours to obtain pitavastatin calcium(358.5 g, 93%, purity 99 area-% HPLC); diastereomeric purity 98.9%(HPLC: YMC-Pack Pro C18; eluent 0.01 M aqueous sodium chloride solution,acetic acid, pH 3.4/methanol; flow rate 0.6 mL/min.; T=40° C.; detectionUV at 245 nM); optical purity: 99.7% (HPLC: Chiralcel OD; eluent,hexane/EtOH/TFA —900/100/0.5; flow rate 1 mL/min.; UV @254 nM). Thisproduct can be re-crystallized as in Example 6B to obtain adiastereomeric purity of 99.8% and an optical purity of >99.9%.

EXAMPLE 8

Seven disilyloxydiene reagents with different R₁ groups have beenevaluated for enantioselectivity in the aldol condensation according tothe procedure set forth in Method 1 of Example 3 to form5(S)-hydroxy-3-ketoesters as follows:

The results are summarized in following table, and show that greaterenantiomeric purity is achieved when R₁ is a linear alkyl group, such asmethyl, ethyl or n-propyl, as compared to a branched alkyl group, suchas isopropyl or isobutyl:

R₁ Yield¹ (%) Optical purity² (%) mp (° C.) Me 62 98 47-51 Et  91³  97³81-84 n-Pr 91 98 Oil i-Pr  74³  83³ 82-83 MeO(CH₂)₂— 90 90 Oil i-Bu 7180 Oil Benzyl 47 88 Oil ¹Isolated yields. ²Determined by HPLC. ³Averageof two experiments.

EXAMPLE 9

5(S)-hydroxy-3-ketoester (S₁′) was prepared using an external recyclereactor. The reactor contained a 0.5-L jacketed vessel equipped with aretreat-curve impeller and temperature sensor to determine the batchtemperature; a recycle pump; a 1″-OD tube packed with solids; twothree-way valves placed, respectively, at the inlet and exit of thetube; connecting tubing to form an external recycle loop; and a dosingpump for adding liquid to the recycle loop

The 1″-OD tube was packed with 5.06 g of 4A mol sieve pellets (Aldrich,Cat. No. 334304, Batch No. 07701 LS) having a diameter of 1.6-mm. The 4Amol sieves were confined to the middle part the 1″-tube using metal meshscreens. The top and bottom of the tube were packed with 3-mm Pyrexglass beads. The sieves were heated to 115° C. under a flow of N₂ (100cm³/min) and kept at this temperature for 12.5 h. Heating wasaccomplished using an electrical heating tape wrapped around the tube.The temperature of the bed of solids was determined using a movable RTDplaced inside a ⅛″ tube mounted co-axially inside the 1″ tube. The twothree-way valves were than switched to allow flow into the tube from thevessel, and out of the tube back to the vessel.

The vessel was purged of air with nitrogen, and charged with:0.4788 g of(S)-Binol, 10.70 g of aldehyde, and 222.03 g of tetrahydrofuran, andsealed. The agitator was turned on at 250 rpm, and the vessel headspacewas purged of air. Flow to the recycle loop was started by turning onthe recycle pump (recycle flow rate=825 cm³/min) and the agitation ratewas reduced to 225 rpm. The batch temperature was controlled at 19° C.

After about 30 min, 45.44 g of a solution (comprised of 1.00 g oftitanium (IV) isopropoxide in 88.95 g of THF) was added using the dosingpump over 6 min. About 20-min after this addition, 4.31 g ofdisilyloxydiene were added over 6 min. After 1 h, a second portion ofdisilyloxydiene (8.9 g over 2 min) was added. After 1 h, a third portionof disilyloxydiene (8.8 g over 2 min) was added. After 2 days, thealdehyde disappearance was complete based on TLC analysis. The vesseland recycle loop were emptied and the reaction mixture was worked up ina separate flask by adding slowly 25 mL of 20% (v/v) aqueoustrifluoroacetic acid keeping the internal temperature below 10° C. (icebath cooling). The mixture was then warmed to room temperature andstirred for 30 minutes. TLC showed conversion of the initialtrimethylsilyl adduct to (S₁′) was complete. 300 mL of t-BuOMe and 200mL of saturated NaHCO₃ were added and the mixture was stirredthoroughly. After filtering the mixture to remove a small amount ofinsolubles, the layers were separated and the organic layer wasrotoevaporated to obtain an oil which was distilled with n-BuOH (2×160mL, 45° C. bath temp, about 20 mbar) to remove ethyl acetoacetate(formed by hydrolysis of the excess disilyloxydiene during workup).Based on NMR analysis of the crude product, an (S₁′) yield of 81.6% wasobtained, and the amount of undesired enantiomer was below the limit ofdetection.

EXAMPLE 10

The vessel recycle loop used in Example 9 was rinsed three times, eachtime with at least 250 mL of tetrahydrofuran, and subsequently dried byflowing nitrogen at room temperature. The dry vessel was charged with:0.48 g of (S)-binol, 10.67 g of aldehyde, and 222 g of tetrahydrofuran.The loop and vessel were purged of air with nitrogen. The agitator wasturned on, and recycle flow was started at the same flow rate as inExample 9, with the batch temperature controlled at 19° C.

After 20 min, 44.96 g of a solution of titanium (IV) isopropoxide(prepared by adding 1 g of the latter to 89.10 g of THF) was added over4 min. After 30 min, 4.4 g of disilyloxydiene were added over 10 min. Asecond portion of disilyloxydiene was added (8.6 g over 2 min) one hourlater. A third disilyloxydiene portion (8.8 g over 2 min) was addedafter 1 hour. After 2 days, the reaction was stopped and the reactionmixture was worked up as in Example 9. The yield of (S₁′), based on NMRanalysis of the crude, was 90%, and the amount of undesired enantiomerwas below the limit of detection.

While the invention has been described with particular reference tocertain embodiments thereof, it will be understood that changes andmodifications may be made by those of ordinary skill within the scopeand spirit of the following claims:

1. A method for preparing compounds having Formula (S₁), (S₂), or (S₃)as follows:

said method comprising condensing a disilyloxydiene having Formula (II)

with an aldehyde having Formula (Q₁), (Q₂), or (Q₃) as follows:

in the presence of a titanium (IV) catalyst of the Formula (IV)

in an inert solvent to obtain a 5(S)-hydroxy-3-ketoester having Formula(S₁), (S₂), or (S₃), wherein R₁ is, independently, an unsubstituted orsubstituted alkyl, cycloalkyl or aralkyl; R₂, R₃, R₄, R₅, R₆ and R₇ are,independently, hydrogen, halogen, hydroxy, optionally substituted alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionallysubstituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy;R₈ is a lower alkyl; the binaphthyl moiety is in the S-configuration; Rand R′ are, independently, a lower alkyl; and M is sodium, lithium orpotassium.
 2. The method according to claim 1, wherein the molar ratioof a disilyloxydiene of Formula (II) to an aldehyde of Formula (Q₁),(Q₂), or (Q₃) initially present in the reaction mixture ranges from 1:1to 6:1.
 3. The method according to claim 1, wherein the disilyloxydieneof Formula (II) is prepared by (a) reacting an acetoacetate of theFormula (VI)

with a silylating agent in the presence of a base and an organic solventto form a silylenolether having Formula (VII)

(b) treating the silylenolether having Formula (VII) with a base and asilylating agent in an inert solvent to form the disilyloxydiene ofFormula (II), wherein R₁ is, independently, an unsubstituted orsubstituted alkyl, cycloalkyl or aralkyl; and R is a lower alkyl.
 4. Themethod according to claim 3, wherein the organic solvent in step (a) ishexane, and the inert solvent in step (b) is diethylether ortetrahydrofuran.
 5. The method according to claim 3, wherein the base instep (a) is triethylamine.
 6. The method according to claim 3, whereinthe base in step (b) is selected from the group consisting of lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.
 7. Themethod according to claim 3, wherein the silylating agent istrimethylsilyl chloride or triethylsilyl chloride.
 8. The methodaccording to claim 1 wherein the titanium (IV) catalyst of Formula (IV)is prepared in situ by reacting titanium (IV) tetraisopropoxide with(S)-2,2′-binaphthol of the Formula (VIII)


9. The method according to claim 8, wherein the molar ratio of thetitanium (IV) catalyst of Formula (IV) to an aldehyde of Formula (II)initially present in the reaction mixture ranges from 0.01:1 to 0.15:1.10. The method according to claim 1, wherein R₁ is lower alkyl, R₂ ishalogen; and R₃, R₄, R₅, R₆ and R₇ are hydrogen.
 11. The methodaccording to claim 10, wherein R₁ is ethyl; and R₂ is fluorine.
 12. Amethod for preparing syn-3(R),5(S)-dihydroxyesters having Formula (V₁),(V₂), or (V₃) as follows:

said method comprising reducing compounds of Formula (S₁), (S₂), or (S₃)in the presence of a di(lower alkyl)methoxyborane, a reducing agent, anda polar solvent, wherein compounds of Formula (S₁), (S₂), or (S₃) asfollows:

wherein R₁ is, independently, an unsubstituted or substituted alkyl,cycloalkyl or aralkyl; and R₂, R₃, R₄, R₅, R₆ and R₇ are, independently,hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl,aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substitutedalkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy.
 13. Themethod according to claim 12, wherein the di(lower alkyl)methoxyboraneis diethylmethoxyborane or dibutyl-methoxyborane.
 14. The methodaccording to claim 12, wherein the polar solvent is selected from thegroup consisting of tetrahydrofuran, methanol, ethanol, isopropanol,butanol, and mixtures thereof.
 15. The method according to claim 12,wherein the reducing agent is sodium borohydride or lithium borohydride.16. A method for preparing calcium salts having Formula (W₁), (W₂), or(W₃) as follows:

said method comprising: (a) condensing a disilyloxydiene of the Formula(II)

with an aldehyde having Formula (Q₁), (Q₂), or (Q₃) as follows:

in the presence of a titanium (IV) catalyst having Formula (IV)

in an inert solvent to form a 5(S)-hydroxy-3-ketoester having Formula(S₁), (S₂), or (S₃) as follows:

(b) reducing the 5(S)hydroxy-3-ketoester having Formula (S₁), (S₂), or(S₃) to a 3(R),5(S)-dihydroxyester in the presence of a di(loweralkyl)methoxyborane, wherein the 3(R),5(S)-dihydroxyester has Formula(V₁), (V₂), or (V₃) as follows:

(c) hydrolyzing the 3(R),5(S)-dihydroxyester having Formula (V₁), (V₂),or (V₃) in the presence of an aqueous base to form an alkali metal salthaving Formula (X₁), (X₂), or (X₃) as follows:

(d) converting the alkali metal salt of Formula (X₁), (X₂), or (X₃) to acalcium salt of Formula (W₁), (W₂), or (W₃), in the presence of acalcium source, wherein R₁ is, independently, an unsubstituted orsubstituted alkyl, cycloalkyl or aralkyl; R₂, R₃, R₄, R₅, R₆ and R₇ are,independently, hydrogen, halogen, hydroxy, optionally substituted alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionallysubstituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy;R₈ is a lower alkyl; the binaphthyl moiety is in the S-configuration, Rand R′ are, independently, a lower alkyl; and M is sodium, lithium orpotassium.
 17. The method according to claim 16, wherein the calciumsource in step (d) is calcium chloride.
 18. A method for preparingcalcium salts having Formula (We), (W₂), or (W₃) as follows:

said method comprising: (a) condensing a disilyloxydiene of the Formula(II)

with an aldehyde having Formula (Q₁), (Q₂), or (Q₃) as follows:

in the presence of a titanium (IV) catalyst having Formula (IV)

in an inert solvent to form a 5(S)-hydroxy-3-ketoester having Formula(S₁), (S₂), or (S₃) as follows:

(b) reducing the 5(S)-hydroxy-3-ketoester having Formula (S₁), (S₂), or(S₃) to form a 3(R),5(S)-dihydroxyester having Formula (V₁), (V₂), or(V₃) as follows:

in the presence of a di(lower alkyl)methoxyborane; (c) cyclizing the3(R),5(S)-dihydroxyester having Formula (V₁), (V₂), or (V₃) to form alactone having Formula (Y₁), (Y₂), or (Y₃) as follows:

and acid addition salts thereof, in the presence of an acid and anaprotic water-miscible solvent; (d) hydrolyzing the lactone havingFormula (Y₁), (Y₂), or (Y₃) or acid addition salts thereof, in thepresence of an aqueous base to form an alkali metal salt having Formula(X₁), (X₂), or (X₃) as follows:

and (e) converting the alkali metal salt of Formula (X₁), (X₂), or (X₃)to a calcium salt of Formula (W₁), (W₂), or (W₃), in the presence of acalcium source, wherein R₁ is, independently, an unsubstituted orsubstituted alkyl, cycloalkyl or aralkyl; R₂, R₃, R₄, R₅, R₆ and R₇ are,independently, hydrogen, halogen, hydroxy, optionally substituted alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionallysubstituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy;R₈ is a lower alkyl; the binaphthyl moiety is in the S-configuration, Rand R′ are, independently, a lower alkyl; and M is sodium, lithium orpotassium.
 19. The method according to claim 18, wherein the acid instep (c) is concentrated hydrochloric acid, the aprotic water-misciblesolvent is acetonitrile, and the acid addition salt thereof is thehydrochloric acid salt.
 20. A method for preparing an alkali metal salthaving Formula (X₁), (X₂), or (X₃) as follows:

said method comprising: (a) condensing a disilyloxydiene of the Formula(II)

with an aldehyde having Formula (Q₁), (Q₂), or (Q₃) as follows:

in the presence of a titanium (IV) catalyst having Formula (IV)

in an inert solvent to form a 5(S)-hydroxy-3-ketoester having Formula(S₁), (S₂), or (S₃) as follows:

(b) reducing the 5(S)-hydroxy-3-ketoester having Formula (S₁), (S₂), or(S₃) to a 3(R),5(S)-dihydroxyester in the presence of a di(loweralkyl)methoxyborane, wherein the 3(R),5(S)-dihydroxyester has Formula(V₁), (V₂), or (V₃) as follows:

(c) hydrolyzing the 3(R),5(S)-dihydroxyester having Formula (V₁), (V₂),or (V₃) in the presence of an aqueous base to form an alkali metal salthaving Formula (X₁), (X₂), or (X₃); wherein R₁ is, independently, anunsubstituted or substituted alkyl, cycloalkyl or aralkyl; R₂, R₃, R₄,R₅, R₆ and R₇ are, independently, hydrogen, halogen, hydroxy, optionallysubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy,heterocyclooxy or heteroaralkoxy; R₈ is a lower alkyl; the binaphthylmoiety is in the S-configuration, R and R′ are, independently, a loweralkyl; and M is sodium, lithium or potassium.
 21. The method accordingto claim 20, wherein the aqueous base in step (c) is sodium hydroxideand M represents sodium.
 22. The method according to claim 20 whichadditionally comprises a molecular sieve in step (a).
 23. The methodaccording to claim 22, wherein water is added to the molecular sieveprior to using the molecular sieve in step (a).
 24. The method accordingto claim 23, wherein the water content of the molecular sieve is fromabout 1 wt % to about 15 wt %, based on the total weight of the titanium(IV) catalyst.
 25. The method according to claim 24, wherein the watercontent of the molecular sieve is from about 2.6 wt % to about 10 wt %.26. The method according to claim 22 wherein the molecular sieve issituated in a fixed bed external to a reaction vessel in which step (a)is conducted, and the reaction mixture in step (a) is passed through thefixed bed.
 27. The method according to claim 26 wherein the molecularsieve is reused.